Abstract/Summary (Animal Models Core?Core 3) Animal models of cystic fibrosis (CF) are critical for the development of effective molecular therapies. In particular, animal models that reproduce the clinical manifestations of CF are necessary for elucidating the pathophysiologically relevant cellular targets for gene therapy, and aid in the development and testing of both gene and cell therapies for CF. The Animal Models Core (AMC) provides support to investigators who use animal models to study CF pathogenesis, as well as to those who develop molecular therapies for CF. Specifically, it provides centralized production, care, breeding, genotyping, and quality control of CF mouse and ferret models used by Center investigators. Additionally, the AMC has served as a conduit for the dissemination of CF pig tissue specimens from other funded programs in the Carver College of Medicine. However, because of the high cost of maintaining CF pigs, the AMC has not established its own colony, instead relying on two established PPGs, directed by Drs. Stoltz and McCray, to gain access to pig samples. The AMC also assists in the management of BSL2 containment and compliance in animal experiments involving recombinant viruses. Technicians within the Core perform the more technically challenging aspects of studies in CF animal models, such as administering viral vectors, glucose clamps, mixed meal tolerance tests, and oral glucose tolerance tests, as well as testing of drugs and harvesting tissue. Recently, the AMC was instrumental in developing new methods of genetic engineering involving the CRISPR/Cas9 system. This new technology circumvents the need for somatic cell nuclear transfer in the generation of ferret models and has enabled the creation of ROSA26 knock-in Cre-reporter ferrets, cell-specific IRES-CreERT2 driver knock-in ferrets, and conditional CFTR-knockout ferrets. These new lines are enabling Center Members to trace the fates of endocrine progenitors in the CF pancreas and to study CFTR function in specific cell populations. Together with a CFTRG551D ferret generated and characterized during the last funding period, these lines are expected to lead to considerable expansion of the services the AMC provides to the research community. During the last 5 years the AMC greatly increased its dissemination of CF ferret tissue to investigators, serving over 70 researchers at or outside UI and disseminating over 3000 specimens, enabling cost-effective broad use of the model. The majority of AMC effort is directed toward CF gene therapy and CF pathophysiology, providing extensive support for research on CF-related diabetes and disease pathology in the lung, pancreas, intestine, vas deferens, and gallbladder.